Design, Synthesis and Evaluation of New Multifunctional Benzothiazoles as Photoprotective, Antioxidant and Antiproliferative Agents

Abstract

A current trend of research in the health field is toward the discovery of multifunctional compounds, capable of interacting with multiple biological targets, thus simplifying multidrug therapies and improving patient compliance. The aim of this work was to synthesize new multifunctional chemical entities bearing a benzothiazole nucleus, a structure that has attracted increasing interest for the great variety of biological actions that it can perform, and already used as a scaffold in several multifunctional drugs. Compounds are reported, divided into two distinct series, synthetized and tested in vitro for the antioxidant, and include UV-filtering and antitumor activities. DPPH and FRAP tests were chosen to outline an antioxidant activity profile against different radical species. The UV-filtering activity was investigated, pre- and post-irradiation, through evaluation of a O/W sunscreen standard formulation containing 3% of the synthetic compounds. The antitumor activity was investigated both on human melanoma cells (Colo-38) and on immortalized human keratinocytes as a control (HaCat). A good antiproliferative profile in terms of IC₅₀ was chosen as a mandatory condition to further investigate apoptosis induction as a possible cytotoxicity mechanism through the Annexin V test. Compound BZTcin4 was endowed with excellent activity and a selectivity profile towards Colo-38, supported by a good antioxidant capacity and an excellent broad-spectrum photoprotective profile.

Keywords: antioxidant; antitumor; benzothiazole derivatives; multifunctional; organic sunscreen UV-filter.

Figure 1

Structures of PBSA (lead UVB-filter) and some of its derivatives.

Scheme 1

Synthesis of compounds BZTidr1–6. Reagents and conditions: (a) N₂H₄·H₂O, EtOH, 1 h, reflux; (b) Ar-CHO, EtOH, 3–8 h, reflux.

Scheme 2

Synthesis of compounds BZTcin1–5. Reagents and conditions: (c) EDC·HCl, HOBt, CH₃CN, overnight, 55–60 °C.

Figure 2

Effect of benzothiazole derivatives on selected cell lines: (panel A) HaCaT cell line; (panel B) melanoma Colo-38 cell line. Each compound was tested at two different concentrations approaching their IC₅₀ value with the Annexin V assay. Triton X-100 was utilized as a positive control (data not shown).

Figure 2

Effect of benzothiazole derivatives on selected cell lines: (panel A) HaCaT cell line; (panel B) melanoma Colo-38 cell line. Each compound was tested at two different concentrations approaching their IC₅₀ value with the Annexin V assay. Triton X-100 was utilized as a positive control (data not shown).